The goal of the present study was to investigate whether a rest period following the end of chronic stress would impact fear extinction. Past research has indicated that chronic stress leads to impairments in the learning and recall of fear conditioning extinction. Moreover, the effects of chronic stress can return to levels similar to controls when a post-stress “rest” period (i.e., undisturbed except for normal husbandry) is given prior to testing. Male rats underwent chronic restraint stress for 6hr/day/21days (STR-IMM). Some rats, underwent a post-stress rest period for 6- or 3-weeks after the end of stress (STR-R6, STR-R3). Control (CON) rats were unrestrained for the duration of the experiment. In Experiment 1, following the stress or rest manipulation, all rats were acclimated to conditioning and extinction contexts, fear conditioned with 3 tone-foot shock pairings, and then had two days of extinction training. All groups froze similarly to the tone across all training sessions. However, STR-R6/R3 froze less in the non-shock context than did STR-IMM or CON. During extinction training, STR-IMM showed high levels of freezing to the non-shock context, leading to a concern they may be generalizing across contexts. Consequently, a follow-up experiment tested for context generalization. In Experiment 2, STR-IMM rats underwent a generalization test in an environment that was either different or the same as the conditioning environment, using STR-R6 as a comparison. STR-IMM and STR-R6 showed similar relative levels of freezing to tone and context, regardless of their conditioning environment to reveal that STR-IMM did not generalize and instead, maybe expressing hypervigilance. Thus, the present study demonstrated the novel finding that a rest period from chronic stress can lead to reduced fear responsiveness in a non-shock environment.

Chronic stress results in functional and structural changes to the hippocampus. Decades of research has led to insights into the mechanisms underlying the chronic stress-induced deficits in hippocampal-mediated cognition and reduction of dendritic complexity of hippocampal neurons. Recently, a considerable focus of chronic stress research has investigated the mechanisms behind the improvements in hippocampal mediated cognition when chronic stress ends and a post-stress rest period is given. Consequently, the goal of this dissertation is to uncover the mechanisms that allow for spatial ability to improve in the aftermath of chronic stress. In chapter 2, the protein brain derived neurotrophic factor (BDNF) was investigated as a mechanism that allows for spatial ability to show improvements following the end of chronic stress. It was found that decreasing the expression of BDNF in the hippocampus prevented spatial memory improvements following a post-stress rest period. Chapter 3 was performed to determine whether hippocampal CA3 apical dendritic complexity requires BDNF to show improvements following a post-stress rest period, and whether a receptor for BDNF, TrkB, mediates the improvements of spatial ability and dendritic complexity in a temporal manner, i.e. during the rest period only. These experiments showed that decreased hippocampal BDNF expression prevented improvements in dendritic complexity, and administration of a TrkB antagonist during the rest period also prevented the improvements in spatial ability and dendritic complexity. In chapter 4, the role of the GABAergic system on spatial ability following chronic stress and a post-stress rest period was investigated. Following chronic stress, it was found that male rats showed impairments on the acquisition phase of the RAWM and this correlated with limbic glutamic acid decarboxylase, a marker for GABA. In chapter 5, a transgenic mouse that expresses a permanent marker on all GABAergic interneurons was used to assess the effects of chronic stress and a post-stress rest period on hippocampal GABAergic neurons. While no changes were found on the total number of GABAergic interneurons, specific subtypes of GABAergic interneurons were affected by stressor manipulations. Collectively, these studies reveal some mechanisms behind the plasticity seen in the hippocampus in response to a post-stress rest period.

We hypothesized that recurrent exposure to a temporal discounting task would habitize participants, so that they become insensitive to framing effects. Temporal discounting is a behavioral trend which describes how people discount the value of a reward dependent on the time until receipt. Participants completed a temporal discounting task weekly for five weeks, to promote formation of a habitual decision strategy. Concomitant with this, we expected that people would shift their decision process from a deliberate, goal-oriented approach that is sensitive to changes in reward outcomes and environmental context, to a simplified, automatic approach that minimizes cognitive effort. We expected that this shift in decision strategy would be evident in a reduced influence of contextual effects on choice outcomes. We tested this hypothesis by leveraging two framing effects \u2014 the date/delay effect and the decimal effect. Consistent with our hypothesis, we find that the date/delay effect is significant on week 1, shows significant changes in week 1 to week 5, and is no longer significant on week 5. The results for the decimal effects were not significant. We discuss these results with respect to the cognitive processes that underlie temporal discounting and self-control.

The present study examined how systemic low doses of nicotine affect the microstructure of food-reinforced behavior in rats. Rats were given an acute saline or nicotine treatment (0.1-0.6 mg/kg, resting at least 48 h between injections), and a chronic saline or nicotine treatment (0.3 mg/kg for 10 consecutive days). Immediately after treatment, rats were required to press a lever to obtain food, whose availability was unpredictable, but programmed at a constant rate (on average every 80 s). Acute nicotine dose-dependently suppressed behavior prior to the delivery of the first reinforcer, but enhanced food-reinforced behavior afterwards. This effect was primarily observed in the time it took rats to initiate food-seeking behavior, and not in the food-seeking behavior itself. A pre-feeding control procedure suggests that these effects cannot be explained only by changes in appetite. Over the course of chronic nicotine exposure, tolerance developed to the suppressive, but not to the enhancing effects of nicotine on food-seeking behavior. These results suggest that ostensive sensitization effects of nicotine on behavior may instead reflect a tolerance for its suppressive effects on behavior.

Chronic stress impairs spatial working memory, attention set-shifting, and response inhibition. The relationship between these functions and the potential underlying neurocircuitry, such as the medial prefrontal cortex (mPFC), needs further research to understand how chronic stress impacts these functions. This study focused on the infralimbic (IL) and prelimbic (PRL) regions of the mPFC, to examine its involvement in two behavioral tasks, fixed minimum interval (FMI) and radial arm water maze (RAWM), following chronic stress, and the relationship between the two paradigms. A previous study failed to find a significant correlation between spatial working memory and response, both functions mediated by the PFC, even though chronic stress disrupted both outcomes. Thus, the purpose of this study was to investigate the functional activation of the mPFC, following chronic stress in these two paradigms, in order to gain an understanding of the neurocircuitry involved within this region. The behavioral outcomes were performed prior to my involvement in the project, and the results corroborate previous findings that chronic stress impairs response inhibition on FMI and spatial working memory on RAWM. My honors thesis involved quantifying the immunohistochemistry-stained tissue to assess the functional activation of the mPFC. Over the course of six months, my work involved identifying the border between IL and PRL regions by overlaying captured images of tissues, starting at a lower magnification of 40x. Afterwards, images were recaptured at higher magnifications (100x) to quantify Fos-like counts of functional activation. No overt changes were found following chronic stress in Fos-like counts after performance on FMI or RAWM. However, response inhibition on the FMI task showed a relationship with the IL function; non-stressed rats displayed a positive correlation between response inhibition and Fos-like profiles. In contrast, chronically stressed rats revealed a negative correlation between response inhibition and Fos-like profiles. The IL cortex is revealed to facilitate extinction of a learned behavior. Thus, these results present a possible interpretation that there is an association, non-stressed rats suppressing a previously learned response, being formed.

Incentive salience is a motivational-cognitive process that can transform an otherwise neutral stimulus into something that is wanted. The prolonged use of nicotine appears to enhance incentive salience; it has been suggested that the nicotinic enhancement of incentive salience contributes to the potential of relapse in individuals with tobacco addiction. In order to determine whether (a) nicotinic enhancement of incentive salience for non-nicotinic stimuli occurs when rats self-administer nicotine and (b) a history of nicotine use facilitates such enhancement, rats were trained in a morning self-administration paradigm (SA), in combination with an afternoon 4-CS Pavlovian conditioned approach task (PCA) for 24 days. SA was followed by extinction and cue reinstatement. Nicotine SA enhanced incentive salience in the PCA. Upon extinction, incentive salience quickly declined to saline levels, indicating that the nicotinic enhancement of incentive salience is transient. Experimenter-administered nicotine enhanced incentive salience similarly regardless of nicotine history, suggesting that a previous history of nicotine use does sensitize the nicotinic enhancement of incentive salience. Taken together, these results suggest that nicotine must be onboard for the expression of nicotinic enhancement of incentive salience. This suggests that the role of incentive salience in the development and relapse of tobacco addiction may need to be revisited.

The use of synthetic cathinones or "bath salts" has risen dramatically in recent years with one of the most popular being Methylendioxypyrovalerone (MDPV). Following the temporary legislative ban on the sale and distribution of this compound , a multitude of other cathinone derivatives have been synthesized. The current study seeks to compare the abuse potential of MDPV with one of the emergent synthetic cathinones 4-methylethcathinone (4-MEC), based on their respective ability to lower current thresholds in an intracranial self-stimulation (ICSS) paradigm. Following acute administration (0.1, 0.5, 1 and 2 mg/kg i.p.) MDPV was found to significantly lower ICSS thresholds at all doses tested (F4,35=11.549, p<0.001). However, following acute administration (0.3,1,3,10,30 mg/kg i.p) 4-MEC produced no significant ICSS threshold depression (F5,135= 0.622, p = 0.684). Together these findings suggest that while MDPV may possess significant abuse potential, other synthetic cathinones such as 4-MEC may have a drastically reduced potential for abuse.

Mammalian olfaction relies on active sniffing, which both shapes and is shaped by olfactory stimuli. Habituation to repeated exposure of an olfactory stimuli is believed to be mediated by decreased sniffing; however, this decrease may be reserved by exposure to novel odorants. Because of this, it may be possible to use sniffing itself as a measure of novelty, and thus as a measure of odorant similarity. Thus, I investigated the use of sniffing to measure habituation, cross-habituation, and odorant similarity. During habituation experiments, increases in sniff rate seen in response to odorant presentation decreased in magnitude between the first and second presentations, suggesting of habituation. Some of this reduction in sniff rate increases was revered by the presentation of a novel odorant in cross-habituations. However the effect sizes in cross-habituation experiments were low, and the variability high, forestalling the conclusion that sniffing accurately measured cross-habituation. I discuss improvements to the experimental protocol that may allow for cross-habituation to be more accurately measured using sniffing alone in future experiments.

Background: Brain regions that mediate learning of a conditioned place preference (CPP) undergo significant development in pre and periadolescence. Consuming a high fat (HF) diet during this developmental period and into adulthood can lead to learning impairments in rodents. The present study tested whether HF diet intake, consumed only in pre and periadolescence, would be sufficient to cause impairments using a CPP procedure.

Methods: Rats were randomly assigned to consume a HF or a low fat (LF) diet during postnatal days (PD) 21-40 and were then placed back on a standard lab chow diet. A 20-day CPP procedure, using HF Cheetos® as the unconditioned stimulus (US), began either the next day (PD 41) or 40 days later (PD 81). A separate group of adult rats were given the HF diet for 20 days beginning on PD 61, and then immediately underwent the 20-day CPP procedure beginning on PD 81.

Results: Pre and periadolescent exposure to a LF diet or adult exposure to a HF diet did not interfere with the development of a HF food-induced CPP, as these groups exhibited robust preferences for the HF Cheetos® food-paired compartment. However, pre and periadolescent exposure to the HF diet impaired the development of a HF food-induced CPP regardless of whether it was assessed immediately or 40 days after the exposure to the HF diet, and despite showing increased consumption of the HF Cheetos® in conditioning.

Conclusions: Intake of a HF diet, consumed only in pre and periadolescence, has long-lasting effects on learning that persist into adulthood.